Lyophilization is a process which has become more common in the pharmaceutical industry in present times as the need to increase the storage life of pharmaceutical products increases. In the past, with relatively inexpensive drugs, or with drugs which are in tablet or capsule form, the shelf life or storage life has not been a significant factor. However, as drugs become more complex and specialized, the need for longer storage life has increased.
Lyophilization is of particular value when the pharmaceutical product is particularly sensitive to solvents such as water. During lyophilization, the product in liquid form is cooled until it is completely frozen, typically to temperatures at or below minus 50.degree. C. Once the product has been completely frozen, the water or other solvent will separate from the solute ingredients. It is then possible to remove the separated water or other solvent from the frozen product by heating the contents slowly, under carefully controlled conditions, and under high vacuum so that the solvent leaves the products through sublimation.
If too much heat is added too quickly, the product will melt. If the rate of sublimation is too slow, the manufacturing cost will make the process unacceptable. It is not desirable to tie up expensive equipment and staff, nor is it desirable to subject the ingredient to an extremely long sublimation cycle. Clearly, optimization for each product and solvent will depend upon the particular ingredients but it is always a goal.
There are two stages in the lyophilization cycle. First, the product must be frozen. It is not generally possible to accurately divide a large quantity of freeze dried product into individual dosages and place those individual doses in separate containers. Rather, the aqueous solution is accurately measured into separate containers and these containers are then placed in the lyophilization apparatus.
Typically, a number of containers are placed on a metal tray, so that heat transfer can be optimized, and then the tray is placed in the lyophilization chamber. Temperature is then reduced until the product and solvent freeze.
The second phase in the lyophilization cycle is the drying process. Drying is accomplished by a mixture of heat transfer and mass transfer at the same time. The drying process is conducted under vacuum so that the vapor pressure of water or other fluids is relatively low. Heat is applied to transform ice crystals into water vapor. This vapor migrates through the rest of the product and escapes out the vacuum vent at the top of the container. Clearly, if a very long period of time is taken, there is plenty of opportunity for the water vapor to escape from the entire dried product. In addition, this is clearly inefficient. If heat energy is applied at too high of a rate, water vapor is produced faster than it can be removed from the dried product. As a result, the product may re-solubalize or may be insufficiently dried because the passageways for the water vapor are closed off.
In a properly run lyophilization process, the shelf temperature, vacuum level, heat transfer, and other variables are optimized and an acceptable, saleable product is produced. Once the proper lyophilization is completed, the stopper is then fully inserted into the container, thereby preserving the integrity of the product. Aluminum or plastic seals and other means for ensuring product integrity are employed to make the container ready for the market place. While the process itself is quite satisfactory, it would be a great advantage in the art if the process could be done faster. Ideally, even though the particular process is optimized, complete lyophilization may take many hours to be completed. It would be highly desirable if this time could be reduced significantly without running any risk of adversely affecting the product in its final form.
Presently, a great number of containers are manufactured for use in the lyophilization process, wherein a liquid is placed in a vial type container, partially stoppered to permit escape of the water vapor during the sublimation step, followed by complete stoppering through the application of force along the axis of the container.
Glass containers have historically been used as pharmaceutical lyophilization containers because glass has the desired clarity, resistance to chemical attack and physical stability. One principal drawback of glass as a container for pharmaceutical products is that the glass containers are not directly usable for intravenous or IV administration to a patient without venting.
Because the glass walls are rigid and do not collapse as the liquid is withdrawn, it is necessary to provide an additional venting mechanism in order to use the same container for storage and administration to the patient. Particularly when hazardous or highly sensitive medicaments are employed, it is not desirable to reconstitute the freeze dried medicine in a glass vial and transfer it to a more flexible plastic container for use in intravenous administration.
Glass containers also have the drawback of potential breakage. If breakage occurs during the lyophilization process in the chamber, glass particles could possibly enter the unstoppered product container, rendering a product that could be dangerous to use in humans.
In some instances, drugs used for treatment of cancer and other diseases are themselves very dangerous. For these toxic, irritating or limited-exposure drugs, breakage of glass containers is considered a serious threat to the health of hospital personnel who work with those drugs on a daily basis.
Nonetheless, while there are many drawbacks to the use of glass in lyophilization processes, to this date, an effective and total solution to all of the problems using non glass containers has not been discovered.
Clarke et al, U.S. Pat. No. 4,415,085, proposes a dry system using flexible bags of two layers of plastics. This system does propose certain advantages of plastic containers over those made from glass. Primarily, the rigidity of glass containers and the need to vent them are listed as two of the major drawbacks. The flexible package of the Clarke et al design is formed from a plastic film laminate having a polyethylene terephthalate film bonded to a medium density polyethylene film. It is clear from reading the Clarke et al patent that an entirely new system would be needed to modify this container for use in a lyophilization processing facility which had previously been designed for glass vials.
Another flexible container which is apparently quite suitable for sterilized medical situations in which blood bags or IV bags are used is shown in Mahal, U.S. Pat. No. 4,479,989. Mahal described the advantages of linear low density polyethylene and other materials suitable for IV bags.
Plastic medical solution containers present different problems for port construction. Two patents which describe port and closure constructions are McPhee, U.S. Pat. Nos. 4,484,916, and 4,592,092. Two other medical storage bags, more suitable for use as blood bags, are described in Herbert, U.S. Pat. Nos. 4,516,977 and 4,561,110. Both of these later patents describe multiple layer bags for medical purposes, in which one of the layers is a polyethylene film.
In summary, while a number of plastic containers have been proposed for use in intravenous administration of medical products, none of these plastic containers appear to be useful as a substitute for the glass vials in conventional lyophilization processes. It is, therefore, an object of this invention to produce such a container. Yet another object of this invention is to provide a flexible container for use in the lyophilization process which is superior to glass as an IV container.
Other objects will appear hereinafter.